Raltegravir, also referred to as Raltegravir free hydroxy, N-(2-(4-(4-fluorobenzylcarbamoyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)propan-2-yl)-5-methyl-1,3,4-oxadiazole-2-carboxamide, having the following formula;
is an antiretroviral drug used to treat HIV infection. Raltegravir targets integrase, an HIV enzyme that integrates the viral genetic material into human chromosomes, a critical step in the pathogenesis of HIV. Raltegravir potassium salt is marketed under the trade name ISENTRESS™ by Merck & Co.
Raltegravir and its preparation are described in U.S. Pat. No. 7,169,780. US Publication No. US 2006/0122205, WO 2010/140156 and WO 2011/024192 describe potassium salt of Raltegravir including amorphous and crystalline forms I, II, III and H1 as well as amorphous and crystalline forms of Raltegravir free-hydroxy.
The present invention relates to salts of Raltegravir, as well as solid state forms of Raltegravir and Raltegravir salts. These properties can be influenced by controlling the conditions under which Raltegravir potassium, Raltegravir sodium, Raltegravir calcium, Raltegravir tert-butyl amine, Raltegravir lithium, Raltegravir diethylamine, Raltegravir diisopropylamine, Raltegravir meglumine and Raltegravir free hydroxy, are obtained in solid form.
Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, thermal behaviors (e.g. measured by thermogravimetric analysis—“TGA”, or differential scanning calorimetry—“DSC”), X-ray diffraction pattern, infrared absorption fingerprint, and solid state NMR spectrum. One or more of these techniques may be used to distinguish different polymorphic forms of a compound.
Discovering new salts and new polymorphic forms and solvates of a pharmaceutical product can provide materials having desirable processing properties, such as ease of handling, ease of processing, storage stability, ease of purification or as desirable intermediate crystal forms that facilitate conversion to other polymorphic forms. New polymorphic forms and solvates of a pharmaceutically useful compound or salts thereof can also provide an opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for formulation optimization, for example by providing a product with different properties, e.g., better processing or handling characteristics, improved dissolution profile, or improved shelf-life. For at least these reasons, there is a need for additional salts and solid state forms of Raltegravir potassium, sodium, calcium, tert-butyl amine, meglumine, lithium, diethylamine and diisopropylamine salts and of Raltegravir free-hydroxy.